| Summary: | 碩士 === 國立中正大學 === 分子生物研究所 === 103 === Myotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by CUG repeatexpansion. Mutant transcrip with expansion attracted RNA binding proteins, resulting in mis-regulation of alternative splicing and physiological toxicity. It has been shown in our laboratory that expanded CUG repeat inducedtoxicity is reversiblein C. elegans. To screen for the genetic modifiers for DM1, we performed genome-wide RNAi screening and identified 15 candidate RNAi clones which can extend the life span of CUG125 worms. Among the 15 disease modifiers, rtel-1, is a DNA helicase. Our preliminary results showed that rtel-1 DNA helicase participated in the expression of expanded trinucleotide repeats.Recent reports showed that DDX5helicases increases binding of RNA binding proteinonto pathological repeats in human myoblasts. On the other hand, DDX6 overexpression significantlyrelieves DM1 mis-splicing and reduces nuclear DMPK-mRNA foci in DM1 patient fibroblasts.There are about 140 DNA/RNA helicase genes in C.elegans.I have re-screened the worms and found thatonly 3 DNA and RNA helicase genes, Dog-1, wrn-1 and F52B5.3,specificallydecreased the expression of expanded CTG repeats and relieved the phenotype of CUG125 worms. Although the underlying mechanism of how helicase genes regulate worm phenotypes remains elusive, our results indicate that the CUG RNA toxicity can be suppressed by modulating the expression level of helicases.
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